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Link Between Inflammation and Cancer

The link between inflammation and cancer was first proposed by Rudolph Virchow in 1863, when he observed leucocytes in neoplastic tissue. This hypothesis has been revisited and studied extensively in recent times, with the relationship between inflammation and cancer appearing increasingly likely. It appears chronic inflammation has a role in all phases of the tumorigenic process, as well as being a risk factor for the development of most cancers. However chronic inflammation can have both tumorigenic and antitumour actions, as well as affecting the immune system. Through a better understanding of the role of chronic inflammation in cancer, the treatment of other chronic inflammatory conditions such as diabetes, cardiovascular disease and rheumatic fever may also be revolutionised.
Chronic inflammation has been shown to have a causative role in the first stage of tumorigenesis, named tumour initiation. In this phase, normal cells are genetically altered to become malignant. The chronic inflammation which causes these changes may be a progression from acute inflammation if the injurious agent has persisted, however most of the time the response is chronic from the outset8. Causes of chronic inflammation include infection, alcohol abuse, acid reflux, asbestos and cigarette smoking. Prolonged inflammation has been shown to cause tumour initiation through multiple mechanisms, the key ones discussed here being free radical production and activation of the NF-?B transcription factor.
In chronically inflamed tissue there is increased production of free radicals such as reactive oxygen intermediates (ROI), hydroxyl radical (OH∙) and superoxide (O2-∙) and reactive nitrogen intermediates (RNI), nitric oxide (NO∙)and peroxynitrite(ONOO-)3. These free radicals may be released from leucocytes and other phagocytic cells infiltrating the inflamed tissue or could be induced from cytokines such as TNF3. These highly unstable molecules have been found to have oncogenic effects via multiple mechanisms such as direct DNA and protein damage, inhibition of apoptosis, mutation of DNA and cellular repair functions [such as p53, a tumour suppressor protein] and also through the promotion of angiogenesis. These mechanisms have also been proven clinically; for example, two weeks of exposure to TNF to nude mice in vitro was found to be sufficient to render cells cable of tumour formation. These effects were attributed to the induction of reactive oxygen. Another study focusing on the effects of chronic inflammation in colitis-associated cancer found that p53 mutations were found in both cancer cells and in inflamed, but nondysplastic epithelium. This suggested that the chronic inflammation associated with colitis was the cause of the genetic changes9. However whilst the free radicals released from leukocytes or induced from cytokines have an important role in tumour initiation, there are other factors contributing as well.
The activity of the NF-?B transcription factor also has a pivotal role in all phases of tumorigenesis, especially in tumour initiation. NF-?B is activated in response to stimulation by proinflammatory cytokines, and it regulates several genes whose products inhibit apoptosis and enhance cell cycle progression, angiogenesis and metastasis5,10. Furthermore, a significant number of NF-?B target genes encode mediators of the innate immune response and inflammation, which includes cytokines, chemokines, proteases and COX-25,10. NF-?B activation, like many inflammatory cytokines, is also subject to a feed forward loop; activation of NF-?B in immune cells induces production of cytokines that activate NF-?B in cancer cells to induce chemokines that attract more inflammatory cells into the tumour. These effects combined mean that NF-?B is an important endogenous tumour promoter, whose effects can be produced via inflammation.
There are a number of important experiments highlighting the importance of inflammation-activated NF-?B activity. Firstly, NF-?B has been shown to be primarily activated by inflammation, represented in one study by cigarette smoke. In this study, when human histiocytic lymphoma cells were treated with cigarette smoke activation of NF-?B occurred in a dose and time dependent manner. The effects of NF-?B inhibition have also been experimentally explored; in a colitis associated model, deletion of IKK? [inhibitor of nuclear factor kappa-B kinase subunit beta a kinase; leads to activation of NF-?B when stimulated] lead to a dramatic decrease in tumour incidence without affecting tumour size. Other studies have shown that when NF-?B activity is blocked; tumour activity is markedly diminished or abolished. These studies are representative of the evidence which shows that chronic inflammation activates NF-?B which in turn causes tumour initiation, regulation of the inflammatory environment and other pro-tumorigenic effects.
Cytokine polymorphisms have also been shown to have an effect on cancer risk. For example Helicobacter pylori induced gastric cancer was shown to be more likely to occur in the presence of certain proinflammatory IL-1 gene cluster polymorphisms. The bacteria H. pylori has also been shown to induce gastric erosion and inflammation prior to mucosal associated lymphoid tumours. The fact that H. pylori is a prerequisite for the association of these polymorphisms with malignancy shows that inflammation is indeed needed for the development of gastric cancer in this setting.
Once the tumour has completed the first phase and become malignant it still requires a background of chronic inflammation to undergo tumour promotion. This is illustrated in the case of a rapidly growing tumour. When tumours grow rapidly they will at one point outstrip their blood supply and become oxygen and nutrient deprived. This results in necrotic cell death at the tumour’s core and the release of proinflammatory mediators such as IL-1 and HMGB13. This inflammatory response promotes neoangiogenesis and provides surviving tumour cells with additional growth factors. Hence inflammatory has an ongoing role in providing nutrients to tumour cells.
The enzyme cyclooxygenase-2 (COX-2) has also been found to play an important part in tumour promotion. The COX-2 enzyme is an inducible carcinogenic found in inflamed and malignant tissue. It is inducible by inflammatory mediators such as IL-1? and NF-?B14. This enzyme is believed to cause inhibition of apoptosis, modulation of cellular adhesion and motility, promotion of angiogenesis and immunosuppression. Epidemiological evidence also implicates COX-2 in many cancers; COX-2 has been found to be enhanced in colorectal cancer, invasive breast tumours and ovarian tumours. Trials have shown that pharmacological inhibition of this enzyme is associated with a reduction of 40-50% in the morbidity and mortality of colorectal cancer. However NSAIDS have been shown to be ineffective in tumours with low or absent COX-2 activity, pointing to COX-2 as its mechanism of action. Hence by blocking the inflammatory stimulation and subsequent tumorigenic actions of COX-2 positive tumours the prevalence of colorectal cancer has been proved to be reduced.
There are many mediators induced by inflammation which assist in tumour promotion, including TNF-alpha and the following interleukins: IL-1, IL-6, IL-8 and IL-182. However there is also considerable overlap between tumour promotion and progression, with many of these mediators also contributing towards the latter. The effects of inflammatory mediators can be broadly classified; firstly, inflammatory cytokines have been shown to cause DNA damage and p53 bypass. These actions have been considered previously with the example of TNF8. Cytokines have also been shown to have actions as growth and survival factors, particularly IL-1 and IL-68. Furthermore they have a role in angiogenesis, with cytokines and chemokines such as TNF, IL-1, IL-6 and IL-8 able to induce the production of angiogenic factors such as VEGF8. Lastly, inflammatory cell production of matrix metalloproteinases (MMPs) has been shown to assist in local tissue invasion by cancer2,8. Transgenic mice lacking MMP were shown to have reduced cellular hyperproliferation and a decreased incidence of invasive tumours. MMPs have been shown to promote cancer invasion by proteolytic cleavage of the extracellular matrix substrates and activate other MMPs to facilitate tumour invasion. Certain chemokines may also induce the migration of tumour cells. It can be seen from the diverse actions of these inflammatory mediators that they do not only act in one dimension; there is overlap between all the phases of tumorigenesis.
Although there are many tumorigenic effects of chronic inflammation, the presence of inflammation may at times be inhibitory to cancer10. A review article examining inflammation concluded that production of an optimal amount of inflammation appeared to be most favourable to cancer growth. Too little inflammation and the tumour showed limited vascularisation and growth, whereas too much inflammation accompanied by a strong monocyte infiltration was associated with cytotoxicity and cancer elimination. This higher inflammation levels have been thought to be associated with enhancement of the cross-presentation of tumour antigens and induction of an antitumour immune response. This enhancement of the antitumour response can be seen in a subset of breast and pancreatic tumours. In these tumours there is a tendency to develop excessive inflammatory infiltration of TAM which is associated with a better prognosis. This has been attributed to the ability of these TAMs to destroy tumour cells, as opposed to contributing to the inflammation and development of the cancer. Further experiments showed that NF-?B was important in determining this balance between the protumour and antitumour properties of macrophages8. However blockage of inflammation may also be delirious. It has been found that administration of TNF blockers in patients with rheumatoid arthritis increases their risk of developing lymphomas16. Therefore care must be taken before altering the balance of inflammation in the body.
The inflammation associated with tumorigenesis also has the potential to alter the activity of the immune system, which in turn may affect tumour severity. Many immune cells can be found in the tumour environment, such as macrophages, dendritic cells (DC), T cells and NK cells. However among these tumour-associated macrophages (TAM) and T cells are frequently the most common leukocytes found in tumours.
TAM is the major inflammatory component of the stroma of many tumours, being capable of promoting angiogenesis, matrix remodelling through MMP production and suppression of adaptive immunity. TAM are especially important in hypoxic regions of tumours, where they increase angiogenesis through the secretion of angiogenic factors such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF)16. The other major pro-tumoral function of TAM is through the suppression of adaptive anti-tumour immune responses. This occurs though blockage of DC maturation and expanded levels of immature myeloid cells. The importance of TAM has been supported by many clinical studies which have found a general correlation between high macrophage tumour content and poor patient prognosis.
T cell responses are ineffective and blunted in the majority of tumours. The suppression of a T cell response occurs through the effects of TAM, as well as the result of defective T cell receptor signalling and increased levels of IL-4 and IL-516. Increased levels of these two interleukins is associated with the T-helper type 2 cell (Th2), which is generally ineffective against tumours. Tumours such as bronchial carcinoma and cervical carcinoma produce mainly IL-4 and IL-5 as opposed to interferon-?, which is associated with Th1 responses and a better prognosis16. Hence the immune system itself may contribute towards the development of certain tumours, as well as causing an ineffective defence against others.
Chronic inflammation appears to have an integral part in tumorigenesis, having a role in all three stages of tumour development. In tumour initiation chronic inflammation causes an increased production of free radicals resulting in the conversion of normal cells to malignant cells. NF-?B is also vital in this stage, as well as having tumorigenic effects in the other phases of tumorigenesis. After this point, increased inflammation as a result of polymorphisms, COX-2 activity, cytokines and immune system function appear to drive tumour development. However inflammation may also be regulated in tumours as a high inflammatory response has been associated with tumour regression. This concept is supported by the pathogenesis of diseases such as psoriasis, which is a chronic inflammatory disease that does not lead to an increase in cancer risk, and may even reduce it. The relationship between inflammation and cancer appears quite complex and intertwined; however when fully elicited will provide breakthroughs in the treatment of all chronic inflammatory conditions.

Therapeutic Effects and Uses of Caffeine

Abstract
Caffeine which is part of many beverages like tea, coffee, energy drinks, cola drinks and chocolates is one of the widely used stimulants by the human population all over the world. The consumption of caffeine varies across age groups. Generally adults follow a pattern in the consumption related to the time of the day, the sleep-wake cycle and other behavioral attributes. Caffeine acts as adenosine A2A receptor antagonist and the blockage of these receptors in striatal basal ganglia is said to be the cause of the stimulant effect of caffeine. Apart from the stimulant and subtle motor effects, caffeine also has several therapeutic effects in relation to its cellular mechanism. Caffeine is said to have neuroprotective properties and can be used as a drug in the treatment of Parkinson’s disease. Caffeine can protect cells from skin cancer resulting from UV radiation since it is able to induce apoptosis of tumorigenic cells. Caffeine therapy was found to be effective in relief from apnea of prematurity in infants. When combined with PTEN treatment, caffeine has a synergistic effect in inducing the apoptosis of human colorectal cancer cells. Caffeine can also help in alleviating of Post dural puncture headache (PDPH). There is a lot of scope to develop caffeine as a potent therapeutic drug and as part of other combinatorial therapies.
Introduction
Caffeine is used as a recreational beverage in the form of coffee as well as a potent stimulator in form of energy drinks in all the parts of the world. Caffeine is a form of methyl xanthine and chemically it is 1,3,7-trimethyIxanthine. This stimulates the CNS.
Based on the action of methylxanthines, 3 possible theories have been proposed regarding why does caffeine have effect on the CNS. Earlier it was thought that the effect of caffeine is due to the rise in levels of cyclic AMP, as caffeine inhibits the enzyme cAMP phosphodiesterase. (1) Also, caffeine may lead to release of Calcium ions from ER and lead to a rise in calcium ions in skeletal muscles. (2) However the most promising theory seems to be that caffeine inhibits adenosine by acting as antagonists to adenosine receptors. (3) To find out which mechanism is the most suitable to explain the action of caffeine, some factors were considered. Caffeine was found to be more potent in the inhibition of adenosine receptors than in the inhibition of cAMP phosphodiesterase. Also, for the release of calcium ions in the skeletal muscles and to observe motor effects, very high concentrations of caffeine would be required. (4)Thus the action of caffeine is attributed mostly to inhibition of adenosine receptors.
Regarding the effective concentration of caffeine , the caffeine concentration in plasma is usually below 100 µM after ingestion of caffeine-rich beverages like coffee etc. However, to observe toxic effects like tachycardia and anxiety, the concentration should be above 200 µM in the plasma.
Cellular Mechanism of Caffeine
Striatal membrane of basal ganglia adenosine A2A receptors lead to reduction in the affinity of D2 receptors for agonists. (5) But also, apart from this, A2A receptors lead to an increase in cAMP production whereas D2 receptors causes a decrease in the production of cAMP. These antagonistic relationships affect striato-Gpe neurons which cause the indirect pathway. The biomarker used to assess the activity of striato-Gpe neurons is enkephalin mRNA in mice studies. Thus caffeine acts against the A2A receptors, which in turn affects the dopamine D2 receptors increasing the motor activity. But some studies suggest that the dopamine D2 receptors may not be involved and the A2a receptors alone can cause the influence on motor activity. (6)
Caffeine counteracts against fatigue during exercise. This happens due to the blockade of A1 receptors , and thus in turn leads to increase in dopamine concentration. Caffeine does not act on the ventral striatum.
Generally the blockage of A2a receptors are more important in relation to the stimulant effect of caffeine. This was proved by the use of knockout mice in which A2A receptor had been knocked out. DPCPX (1,3-dipropyl-8-cyclopentylxanthine) was used, which is antagonist for A1 receptors. After the administration of caffeine a lower locomotor activity was noticed in comparison to wild type mice.
To study the role of dopamine in the action of caffeine, reserpine and also D1 and D2 receptor antagonists were used was used to study the effect
Thus caffeine acts on striato-Gpe pathway and caffeine acts as an adenosine A2A receptor antagonist. The levels of addiction to caffeine is a matter of discussion since there is almost no tolerance to the adenosine A2A receptors. So the withdrawal symptoms of caffeine may be linked to blockade of A1 receptors. (5)
Caffeine consumption by human population
People across the world consume caffeine in the form of various beverages, like tea and coffee, cola drinks, chocolate and energy drinks . A statistical study was conducted in 500 adults of Italian origin ( about 280 males and 300 females). Caffeine intake and other factors ( like smoking cigarettes along with caffeine consumption) were studied. It was found out that males had higher amount of caffeine in a day as compare to females. In this study, the work pattern of the sample population hasn’t been considered. About the time of the day most (about 90%) of the people had caffeine in morning and afternoon and mostly in the form of tea and coffee. The time of the day and the sleep-waking pattern also influences caffeine intake which has been called as “morningness” and “eveningness” according to the time people woke up and had coffee/tea. The lesser forms of caffeine intake comprised of cola drinks, chocolate and energy drinks. Smoking of cigarettes was linked to caffeine consumptions as a higher number of smokers had much more caffeine intake in comparison to non-smokers. (7)
Therapeutic Effects of caffeine
Caffeine and Parkinson’s disease
Parkinson’s disease is one of the most common neurodegenerative disorder which results in degeneration of neurons of the basal ganglia and other disturbances like tremors, rigidity, bradykinesia generally in adults above the age of 45 years. The current therapy involving levodopa is not effective at the efficacy reduces with time and it is also associated with side effects. The biomarker for the efficacy of the therapy is the induction of motor activity on the lesion side which is in turn due to dopamine transmission. Since caffeine acts as an adenosine A2A receptor antagonist, further investigation is possible to develop caffeine as an anti-parkinson’s drug. (13) However suitable measures need to be taken to prevent side effects like anxiety and cardiovascular effects. Caffeine also has neuroprotective properties and ability to reduce glutamate toxicity. (5)
Caffeine prevents skin cancer
The topical or oral application of caffeine is found to destroy UV damaged keratinocytes. This is according to a study carried out on mice. Caffeine augments the apoptosis of UV damaged keratinocytes of the skin and , can have applications in preventing skin cancer. This study is significant because the anti-cancer properties of caffeine were already studied based on papers (1986 Jacobsen et al, 2007 Abel et al.). Regarding the cellular mechanisms , it was found out none of the known mechanisms like effect of caffeine on cyclic AMP levels etc., contribute to this effect . One of the mechanisms is the inhibition of ATR, which was found out based on in vitro and in vivo studies. ATR also targets checkpoint kinase 1 (Chk1), which also gets inhibited. Also, p53 mutant skin cells were used to conclude that p53 gene does not have any effect in this pathway. The future prospects of this study can be to include caffeine in sunscreen applications to reduce skin damage by UV light and as potential skin cancer preventing medicine. (8)
Caffeine therapy in Apnea of Prematurity
Apnea which occurs at prematurity is the difficulty and then subsequent stoppage of breathing which occurs in infants who do not complete their gestation period and are born at less than 34 weeks. Caffeine was found to reduce the intensity of apnea and the rate at which it happens. Also, it negates the need for mechanical ventilation in the initial week of the therapy. Caffeine citrate injections were given to about 2006 infants , and parameters like birth weight etc. were measured to find out the effect of caffeine on bronchopulmonary dysplasia . (9) These experiments were done and compared with placebo studies. Also, according the study by the author along the same lines, when premature infants were treated with caffeine therapy, the incidence of cerebral palsy and cognitive delay was reduced. (10)
PTEN Treatment combined with caffeine
We have already seen that caffeine can destroy cells whose DNA has been damaged by effects such as UV radiation. It is also seen that caffeine can destroy cancer cells also by enhancing the effect of anti-cancer agents. This is the apoptotic effect of caffeine on cancer cells, which is carried out by inhibition of ataxia-telangiectasia-mutated (ATM) and ATR kinase (Rad3-related) activity at cell cycle check points. Thus if caffeine is combined with other anti-cancer agents, it can help in enhancing their effect. Many studies have been conducted regarding the effect of PTEN ( tumor suppressor gene located in chromosome 10). PTEN is said to suppress tumor and cellular proliferation of cancer cells by arresting the cell cycle at G1 . When a combined application of caffeine was given along with PTEN , it created a synergistic effect and lead to apoptosis of cancer cells of human colorectal cancer. But it did not have any effect on normal cells. Thus this can be an effective combinatorial therapy to destroy tumorigenic cells. (11)
Caffeine based therapy in Post dural puncture headache
Caffeine can help in alleviating of Post dural puncture headache (PDPH). A study found out that about 300mg of an oral dose of caffeine can significantly help in the treatment of PDPH in the early stages. Also, it mentioned that oral form of caffeine therapy is more safe and efficacious in the treatment of PDPH. (12)
Future Directions
All of these findings state that caffeine is a potent drug which has a lot of physiological effects on our body. It is entirely safe to consume in moderation since the concentration in plasma of caffeine is usually below 100 µM . When used as a form of therapy or with other drugs as a combinatorial treatment, caffeine can have many therapeutic effects. Thus the future work can be in medical research related to caffeine.
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